Treatment of Alzheimer’s Dementia with Donepezil Psych 4080 March 6, 2007

Treatment of Alzheimer’s Treatment of Alzheimer’s Dementia with Donepezil Dementia with Donepezil

Psych 4080Psych 4080

March 6, 2007March 6, 2007

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OutlineOutline

Cholinesterase Enzymes & InhibitorsCholinesterase Enzymes & Inhibitors DonepezilDonepezil Experimental StudiesExperimental Studies Advantages / DisadvantagesAdvantages / Disadvantages

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Cholinesterase EnzymeCholinesterase Enzyme

Enzyme that catalyzes the hydrolysis of Enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) the neurotransmitter acetylcholine (ACh) into choline & acetic acid into choline & acetic acid

Hydrolysis is important because it Hydrolysis is important because it allows the cholinergic neuron to return allows the cholinergic neuron to return to resting state after its activation.to resting state after its activation.

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Add H2O

Hydrolysis

ACh

Acetic Acid Choline

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Types of CholinesteraseTypes of Cholinesterase

1)1) Psuedocholinesterase Psuedocholinesterase Also known as butyrylcholinesterase Also known as butyrylcholinesterase

(BuChE)(BuChE) Found primary in liverFound primary in liver Selectively hydrolyzes Selectively hydrolyzes

butyrylcholinesterase fasterbutyrylcholinesterase faster

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Types of CholinesteraseTypes of Cholinesterase

2)2) Acetylcholinesterase (AChE)Acetylcholinesterase (AChE) Also known as RBC cholinesteraseAlso known as RBC cholinesterase Found primary in blood & neural Found primary in blood & neural

synapsesynapse Hydrolyzes ACh fasterHydrolyzes ACh faster

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Acetylcholinesterase Acetylcholinesterase Inhibitors (AChEI)Inhibitors (AChEI)

AChE-inhibitors reduce the rate at which AChE-inhibitors reduce the rate at which ACh is broken down.ACh is broken down.

Thus, INCREASE in concentration of ACh in Thus, INCREASE in concentration of ACh in the brain.the brain.

Examples:Examples:

-- Tacrine-- Tacrine

-- Galantatime (Razadyne, Reminyl, -- Galantatime (Razadyne, Reminyl, Nivalin)Nivalin)

-- Rivastigmine (Exelon)-- Rivastigmine (Exelon)

-- Donepezil HCl (Aricept)-- Donepezil HCl (Aricept)

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DonepezilDonepezil Aricept (Pfizer)Aricept (Pfizer) Oral bioavailability: 100%Oral bioavailability: 100% tt1/21/2 Half-life: 70 hrs Half-life: 70 hrs ttmaxmax: 3-5 hrs: 3-5 hrs Best tolerated drug among its classBest tolerated drug among its class Simple to use Simple to use No effect of food on the absorption of No effect of food on the absorption of the drugthe drug

High affinity for the CNS & less effect High affinity for the CNS & less effect on the peripheryon the periphery

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DonepezilDonepezil 2 strengths: 2 strengths: -- 5mg-- 5mg-- 10mg-- 10mg

Price: ~ $175.00 / bottle (30 Price: ~ $175.00 / bottle (30 tab/bottle)tab/bottle)

2 Forms:2 Forms:-- Tablets-- Tablets-- Aricept RDT (Rapid disintegrating -- Aricept RDT (Rapid disintegrating tablets)tablets)

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DonepezilDonepezil Chemical structure / formulaChemical structure / formula

CC2424HH2929NONO33HClHCl

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DonepezilDonepezil Donepezil is the 2Donepezil is the 2ndnd ChEI that was approved ChEI that was approved

by FDA for the treatment of mild to moderate by FDA for the treatment of mild to moderate Alzheimer's in 1996Alzheimer's in 1996

Was shown in studies to help cognition & Was shown in studies to help cognition & function, which includes effects on memory & function, which includes effects on memory & performing everyday tasks performing everyday tasks

Side effectsSide effects• Nausea Nausea • Vomit Vomit • Diarrhea Diarrhea • Insomnia Insomnia • Muscle cramps Muscle cramps • Lose of appetite Lose of appetite • Fatigue Fatigue • DizzinessDizziness

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DonepezilDonepezil Improves cholinergic synaptic function Improves cholinergic synaptic function by increasing ACh at the synaptic cleft.by increasing ACh at the synaptic cleft.

-- Thus, augmenting the function of the -- Thus, augmenting the function of the cholinergic cholinergic receptorsreceptors

Brain areas affected:Brain areas affected:-- Temporopariatal cortex-- Temporopariatal cortex

-- Frontal lobes-- Frontal lobes

-- Basil ganglia-- Basil ganglia

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Krishnan, et. al. (2003). “Randomized, Placebo-Krishnan, et. al. (2003). “Randomized, Placebo-Controlled Trial of the Effects of Donepezil on Controlled Trial of the Effects of Donepezil on

Neuronal Markers & Hippocampal Volumes in Neuronal Markers & Hippocampal Volumes in Alzheimer’s Disease”Alzheimer’s Disease”

STUDY #1STUDY #1ObjectiveObjective

-- Examine the effects of AChEI donepezil on AD -- Examine the effects of AChEI donepezil on AD patientspatients-- Measure changes in concentrations of brain -- Measure changes in concentrations of brain metabolitesmetabolites

N-acetylaspartate & myo-inositolN-acetylaspartate & myo-inositol Measured w/ Proton Magnetic Resonance Measured w/ Proton Magnetic Resonance SpectroscopySpectroscopy

-- Measure changes in cognition -- Measure changes in cognition (ADAS) Alzheimer’s Disease Assessment Scale – (ADAS) Alzheimer’s Disease Assessment Scale – cognitive subscale = (0-70)cognitive subscale = (0-70)

Tested areas of memory, language, & praxis Tested areas of memory, language, & praxis functionsfunctions

-- Measure the hippocampal volumes-- Measure the hippocampal volumes Left, right, total volumesLeft, right, total volumes MRIMRI

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Krishnan et al. (2003)Krishnan et al. (2003)

PatientsPatients

-- 67 patients (34 treated / 33 placebo)-- 67 patients (34 treated / 33 placebo) Women (at least 2 yrs postmenopausal or Women (at least 2 yrs postmenopausal or surgically sterile)surgically sterile)

MenMen 50 yrs old and over50 yrs old and over Clinical Dementia Rating (CDR)= 1 (mild) or Clinical Dementia Rating (CDR)= 1 (mild) or 2 (moderate).2 (moderate).

Mini-mental State Exam (MMSE) = 10 to 26 Mini-mental State Exam (MMSE) = 10 to 26 Hachinski = <= 4 Hachinski = <= 4 No pacemakers, metal within body, No pacemakers, metal within body, claustrophobicclaustrophobic

People w/ other primary mental disorder & People w/ other primary mental disorder & cerebrovascular disease are excludedcerebrovascular disease are excluded

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MethodMethod Randomized, double blind, placebo-Randomized, double blind, placebo-controlled, parallel group study.controlled, parallel group study.

24 weeks, reevaluated at 6 wks interval24 weeks, reevaluated at 6 wks interval Followed by 6 wk single-blind placebo-Followed by 6 wk single-blind placebo-washout period washout period

Placebo & donepezil groupPlacebo & donepezil group

-- Donepezil group received 5mg/day -- Donepezil group received 5mg/day (5mg/placebo pills) for first 28 days.(5mg/placebo pills) for first 28 days.

-- Then 10mg/day afterwards (5mg/5mg -- Then 10mg/day afterwards (5mg/5mg pills)pills)

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ResultsResults 51 (76%) total 51 (76%) total

completed the completed the studystudy

30% in placebo 30% in placebo group group discontinueddiscontinued

18% in 18% in donepezil donepezil group group discontinueddiscontinued

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Hippocampal VolumesHippocampal Volumes

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2020

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N-acetylaspartate N-acetylaspartate concentrationsconcentrations

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Myo-inositol ConcentrationsMyo-inositol Concentrations

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ADAS-cog ADAS-cog subscalesubscale

Significant Significant improvement in improvement in cognition in cognition in donepezil group donepezil group compared to compared to placeboplacebo

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Mechanisms that affect the increase in the Mechanisms that affect the increase in the metabolites & the slow decrease in the metabolites & the slow decrease in the hippocampal volume is still uncertain.hippocampal volume is still uncertain.

A possible mechanism that donepezil can A possible mechanism that donepezil can exert its effects may be involve in the exert its effects may be involve in the processing of amyloid precursor protein processing of amyloid precursor protein (APP).(APP).-- Some evidence suggest that ChEIs -- Some evidence suggest that ChEIs decreases the decreases the

formation of the APP.formation of the APP.-- So, decrease in -- So, decrease in ββ-amyloid accumulation-amyloid accumulation-- Therefore, there would be a slow down the -- Therefore, there would be a slow down the

neurodegenerative process neurodegenerative process stabilize stabilize hippocampal hippocampal volume.volume.

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Cholinesterase may be involved in the Cholinesterase may be involved in the structure & integrity of the amyloid structure & integrity of the amyloid plaques & neurofibrillary tanglesplaques & neurofibrillary tangles

-- Thus, ChEIs can slow the progression of -- Thus, ChEIs can slow the progression of dementiadementia

-- Still uncertain because evidences are -- Still uncertain because evidences are based on based on postmortem, in vitro, & postmortem, in vitro, & experimental animal studies.experimental animal studies.

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LimitationsLimitations-- small number of patients-- small number of patients

Cannot detect small effectsCannot detect small effects

-- no multiple comparisons-- no multiple comparisons

-- Large variance in N-acetylaspartate -- Large variance in N-acetylaspartate concentration may concentration may

explain why there were differences in explain why there were differences in the specific the specific brain regions but not in brain regions but not in cortical areacortical area

Cortical areasCortical areas is a composite of is a composite of several areas.several areas.

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Winblad B, et al. (2001) A 1-year, randomized, Winblad B, et al. (2001) A 1-year, randomized, placebo-controlled study of donepezil in placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology patients with mild to moderate AD. Neurology 2001;57:489-95.2001;57:489-95.

STUDY #2STUDY #2 Double blind, placebo-controlledDouble blind, placebo-controlled 1 year study1 year study

Objective:Objective: Examine the effects of donepezil on the loss Examine the effects of donepezil on the loss

of motor function in mild to moderate AD of motor function in mild to moderate AD patientspatients

PatientsPatients 432 patients432 patients

-- 214 treated w/ donepezil-- 214 treated w/ donepezil

-- 217 w/ placebo-- 217 w/ placebo Avg. age: 75 yrs old (49-94 yrs range)Avg. age: 75 yrs old (49-94 yrs range)

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Winblad B, et al. (2001)Winblad B, et al. (2001)

MethodMethod 5 mg/day for 4 wks, 10 mg/day afterward5 mg/day for 4 wks, 10 mg/day afterward Functional capacities evaluated w/ 2 scales:Functional capacities evaluated w/ 2 scales:

1) Alzheimer’s Disease Functional Assessment 1) Alzheimer’s Disease Functional Assessment & Change & Change Scale (ADFACS) Scale (ADFACS)

-- assess basic activities of daily -- assess basic activities of daily living (ADL) & living (ADL) & instrumental ADLs instrumental ADLs (IADL)(IADL)

dressing, using telephone, etc.dressing, using telephone, etc.

2) Clinical Dementia Rating (CDR)2) Clinical Dementia Rating (CDR)

-- assess cognition & ADL-- assess cognition & ADL

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Winblad B, et al. (2001)Winblad B, et al. (2001)

Patients were assessed at nine 6-wk Patients were assessed at nine 6-wk intervalsintervals

Were attrited from the study if any of Were attrited from the study if any of the following criteria were met:the following criteria were met:

1)1) Decline in the ability to perform 1 or more Decline in the ability to perform 1 or more of the ADLs present at baseline.of the ADLs present at baseline.

2)2) Decline in the ability to perform 20% or Decline in the ability to perform 20% or more of the IADLs at baseline.more of the IADLs at baseline.

3)3) Decline in CDR score.Decline in CDR score. The proportion of patients that The proportion of patients that

discontinued was significantly greater discontinued was significantly greater in the placebo (56%) compared to in the placebo (56%) compared to donepezil (41%). donepezil (41%).

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Y-axis = Y-axis = proportions of proportions of patients patients remaining in remaining in the study at the study at various times various times following following treatment treatment initiation.initiation.

Significant Significant effect of effect of donepezil on donepezil on motor motor functions.functions.

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DonepezilDonepezil AdvantagesAdvantages

-- Good -- Good bioavailabilitybioavailability

-- Absorption not -- Absorption not affected affected by by food.food.

-- Long half life-- Long half life

-- Non-life -- Non-life threatening side threatening side

effects.effects.

-- Improves cognitive -- Improves cognitive & motor & motor functionsfunctions

-- Not too costly-- Not too costly

DisadvantagesDisadvantages

-- if stop -- if stop treatment, brain treatment, brain atrophy may progress.atrophy may progress.

-- Only a treatment -- Only a treatment for mild for mild to to moderate AD.moderate AD.

-- Not a cure for -- Not a cure for AD, only AD, only slows slows progression.progression.

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ConclusionConclusion AD is progressive, & interventions require different AD is progressive, & interventions require different

assessments at different stages of the disease to assessments at different stages of the disease to see what is suitable for each individual.see what is suitable for each individual.

More studies are to be done on the neuropathology of More studies are to be done on the neuropathology of AD, so a more effective method can be derive to AD, so a more effective method can be derive to treat severe AD.treat severe AD.

More studies are to be done on the effects of More studies are to be done on the effects of donepezil:donepezil:

-- on different races & genders.-- on different races & genders.

-- in combinations with other treatments -- in combinations with other treatments (psychosocial, drugs)(psychosocial, drugs)

Compared to other drugs, donepezil seems to be the Compared to other drugs, donepezil seems to be the most beneficial, even it does not cure AD.most beneficial, even it does not cure AD.

-- Allows AD individuals to delay the progression of -- Allows AD individuals to delay the progression of AD & AD & improving their cognitive & motor functions.improving their cognitive & motor functions.

Documents

Treatment of Alzheimer’s Dementia with Donepezil Psych 4080 March 6, 2007